Drug resistance is the central problem of cancer chemotherapy. Clinically effective combination chemotherapy can cause impressive objective tumor response rates, including complete tumor regressions, but some cancer cells are of lesser sensitivity to the agent (i.e., are drug-resistant), are only damaged, recover, and re-grow. The delayed tumor recurrence yields only a short remissions period with little improvement in survival time.
There are many mechanisms of drug resistance. Multiple independent mechanisms of drug resistance may coexist in a population of tumor cells as well as in the same cancer cells, as they arise from multiple genetic changes in single cell clones, and are part of the heterogeneity of the neoplastic process. Mechanisms of drug resistance have been largely identified, and this knowledge has suggested many specific approaches to overcoming one or another type of clinical drug resistance, but these attempts have failed as they also potentiate drug toxicity towards normal tissues.
The therapeutic research strategy for several decades has been that the administration of multiple drugs with different properties and mechanisms of action at optimal doses and intervals should result in cells resistant to one class of drug being killed by another drug in the regimen. However, the extensive, clinical data over these decades has evidenced only a minor impact on treatment outcome along with troublesome and serious toxic side effects (e.g., emesis, diarrhea, alopecia, asthenia, fatigue, myelosuppression, febrile netropenia requiring hospitalization, neurosensory and neuromotor disturbances, arthralgias and myalgias, heart failure, and treatment-related deaths). Despite the long dismal history of repeated failures to meaningfully improve survival rates by aggressive combination chemotherapy with non-cross-reacting drugs, hope is nevertheless expressed that the future will be different with the new molecularly targeted agents.
However, no matter how many effective mechanistically-different anticancer agents there are, and no matter how superior their therapeutic index, cancer cell demise occurs by only two cell death pathways (necrosis or apoptosis). If the latter two cell death mechanisms are attenuated by drug resistance mechanisms (e.g. p-glycoprotein and/or glutathione prevent intracellular drug levels reaching concentration levels sufficient to fully activate the necrosis pathway; caspase deletions and endogenous caspase inhibitors prevent completion of apoptosis), these tumor cells are only sublethally injured, recover, and proliferate to kill the patient. The history of the results of these clinical trials is therapeutic equivalence between different combination chemotherapy “doublets” and “triplets”. The repeated failures of this approach to overcoming clinical drug resistance—i.e., the lack of clinically relevant differences in overall survival—means only continuance of palliative treatment with decisions tailored individually around such issues as differences in toxicity profiles, patients' age and performance status, and quality of life.
New agents, no matter a new molecular target or superior therapeutic index, can only kill cancer cells if there is completion of the cell death pathways through death's door. In drug-resistant cells, it is not the activation of their cell death pathways by clinically effective anticancer agents that is at fault, but rather pathway completion to death of the cell. This reality suggests that continuance of this failed strategy utilizing only aggressive combination chemotherapy with non-cross-reacting drug-will likely result in—to quote Yogi Berra—“déjà vu all over again”.
The above facts suggest the development of a treatment (co-administered with the initiation of activity in the cell death pathways by anticancer agents) that complements (augments) the agent-induced initiation of activity in cell death pathways to completion; namely, to cell death. That treatment, focused on severe ATP depletion, has been developed and proven at the preclinical level, and is about to undergo validation by clinical trial with clinical supplies of the ATP-depleting regimen provided by the NCI RAID grant mechanisms.
Heterogeneous neoplastic cell populations likely contain cancer cells of variable sensitivity to the anticancer agents. Less sensitive cells would not receive enough damage to reduce ATP to low levels sufficient to cause necrotic death. We hypothesized that biochemical modulation to further depress ATP to lower lethal-inducing levels would kill these sublethally-injured cells, augment tumor regressions, and perhaps even yield some cures.